Rhonda: Hello everyone, I'm very excited to be sitting here with Dr. Peter Attia who has a medical degree from Stanford University. And he has done a residency in surgery, I believe, and also some research in surgical oncology with Dr. Steven Rosenberg, I believe. Very interesting background, broad interests. I know of him from being on Tim Ferriss' podcast, where he talked a lot about some of his self-experimentation using a variety of different dietary techniques. But I'm really excited to talk with Peter today because we have a lot of overlap in our interest in longevity, particularly the role of diet, nutrition, and other lifestyle factors like sleep, exercise, stress in longevity. So thanks for being here, Peter.

Peter: Sure.

Rhonda: So maybe we could start a little bit with what are you eating, then, to try to delay the aging process like what is...so diet obviously plays a very important role in aging and I'm trying to figure out exactly the best diet to eat and talk a little bit about what I think, but I'd love to get some of your thoughts.

Peter: So I mean think the short answer is we don't know definitively, and I don't think we're going to know definitively if you define "definitively" as a randomized clinical trial of longevity in humans. We have to posit that we're never going to figure that out. So instead we have to rely on proxies. So we look at proxies in animals where you can do virtually anything you want in a totally controlled setting but then you run the risk of two things. One, are you identifying diets that are clinically and biologically meaningful to your host? For example, if you put a humanized diet into a mouse what you learn may or may not extrapolate to the human.

And then secondly, you're really hindered by the idea that you're studying that animal in an artificial environment and when you reduce the risk of a subset of death, a subset of causes of death which is effectively metabolic disease, you're often unable to measure what in my opinion is an underappreciated risk that comes on, which is, sort of, the more sudden and traumatic causes of death that we take for granted, especially in the case of caloric restriction. So that's the problem with animals. Then what we do in humans is we kind of rely on our best proxy biomarkers that we think reflect the systems that drive aging and we can measure those things over time and sort of estimate what we think is the effective this dietary change or that dietary change or this lifestyle change or that drug change on those things.

And so I basically try to focus my efforts on, sort of, converging those two worlds but acknowledging that we're never going to know the answer for certain and we're going to have to use our best judgment around those things and hope that in time certain other things do become available. For example, it would be really great if there is a way in the blood to measure the activity of mTOR. We don't have that. It would also be great if we could measure other growth pathways like the RAS pathway without having to rely on tissue biopsies and things like that.

Rhonda: So just for people that don't know what mTOR is, can you explain why that's really important?

Peter: Yes. So there are probably, depending on who you talk with, I would say there are two or three major growth pathways in the body that are, kind of, responsible for growth both in the positive sense and in the pathologic sense. The two that I focus on the most are the IGF pathway and the mTOR pathway. Now, mTOR stands for mammalian target of rapamycin. I think for the sake of time I will not tell my favorite story, which is a story that is both the discovery of rapamycin and perhaps more interestingly the elucidation of how it worked. But suffice it to say the compound rapamycin was identified first long before a really amazing guy named David Sabatini as a PhD student at Hopkins in 1993, 1994 as a side project in a lab made the discovery that this thing, rapamycin, was actually working by inhibiting a protein complex of which TOR, target of rapamycin, as it became named was the central piece.

We now know today that it can form onto two complexes. One is called mTOR complex 1 or mTORC1 and the other is mTOR complex 2, mTORC2, and we also know that it exists in different tissues and it has different activities in different tissues. Like most things in the body, too much or too little is a bad thing. So if you have no mTORC1, for example, in your muscles, you'd wither away and that would be a debilitating condition. In fact, for people with muscular dystrophy one of the things you want to do is figure out how to alter that pathway. But similarly, we know that overactivity is predisposing us to aging and, of course, certain diseases of aging like cancer.

Rhonda: So for people that...you know when Peter mentioned that if you don't have any mTORC1 activity you might cause muscle wasting, well, that's because mTOR does a very important role in protein synthesis. And what's very interesting is that both the two pathways that you mentioned in being evolved in aging, mTOR and IGF-1, IGF-1 actually increases mTOR activity so you know they're in this...

Peter: Yeah. These aren't independent pathways, yeah.

Rhonda: Right. And what's also very interesting is that they're both regulated by amino acid intake, right?

Peter: Yes.

Rhonda: So IGF-1 is also a growth factor that you do need as well. So it's one of those things where you don't have any IGF-1, well you're going to be in trouble. I mean, there's a lot of positive things about IGF-1, muscle growth, muscle repair, neuronal growth. But too much IGF-1 also can allow damaged cells to continue growing. But are you familiar with, like, any of the dietary nutritional research on IGF-1 and mTOR and specifically with amino acids and how...

Peter: Yeah. I mean that's, sort of, my biggest obsession, I think, is probably around those topics. So it's complicated. I think we have probably a better understanding of mTOR. I mean I think it's very clear that mTOR is amino acid driven. In fact, what's today? Friday? Last Thursday, eight days ago, David Sabatini and his group at MIT published a paper in "Science" that identified the amino acid sensor for mTORC1. Now, it's always been suspected what it was, which was leucine was the highest affinity, but in fact he's now crystallized that structure. So if you even think about it through the lens of, like, "Why do bodybuilders or people who love lifting weights, want to take Branched-Chain Amino Acids while they're exercising?" The reason is largely through this empirical observation that it enhances muscles growth and/or prevents muscle degradation during exercise.

What I think is really interesting is that we now know exactly what's going on. So the Branched-Chain Amino Acids, there are three, leucine, isoleucine, and valine. It turns out that isoleucine and valine are virtually irrelevant. It's pretty much all leucine. And what's really clever just from an evolutionary perspective is that mTORC in muscle has a much higher affinity for leucine than mTORC1 in fat or in hepatocytes. Now, that's a good thing because you'd like to believe that in times of nutrient deprivation even a trace sign of leucine should preferentially provide the muscle with its growth signal before providing the adipocyte or hepatocyte.

So from a nutrient-sensing pathway, what you could infer from that is too little leucine, probably a bad thing, too much leucine, probably a bad thing. Now, what too much and too little are I think remains to be seen.

The other thing to keep in mind is...you know, because one of the questions a friend of mine asked me recently, actually a mutual friend, Tim Ferris, is "Can we take too much leucine during a workout?" And again, I don't think we know the answer but extrapolating from the animal data I think 5 grams of leucine during a workout, probably not harmful. And it also doesn't stick around very long because when we take amino acids in a workout, if you, sort of, sip them throughout the workout you're taking a free amino acid, so it's got a relatively short stay in the body. In fact, one of the pharmacointerests on this front, which is to treat diseases of muscular wasting, is to actually come up with molecules that are not necessarily more potent agonists of the leucine receptor but would stick around a lot longer. Because that's actually the problem with the nutrition side, is we can't keep leucine around long enough to stimulate muscle growth. Okay. So that's the easy story.

Now the hard one, IGF. Okay. So two schools of thought on this, I am in one camp but I will acknowledge the other camp. One camp says IGF-1 is driven exclusively by amino acids. The other camp says, no, it's actually driven by amino acids and carbohydrates. And carbohydrates indirectly via insulin. So...

Rhonda: Why are those mutually exclusive? I mean...

Peter: The way I define it when I'm...there are certain people who I will not name that are prominent in the field who will argue that the carbohydrates play no role, it's virtually all protein.

Rhonda: But there is a role that they do play that's been shown, depending on...

Peter: I believe it has been shown but, I mean, there are wonderfully erudite people in this field who believe it is entirely an amino acid issue. And it is true, methionine has probably been shown to be the most active amino acid in driving IGF pathway. However, as it sounds like you agree, it's pretty clear that as insulin levels go down IGFBP-3 goes up...sorry, as IGF binding protein 3 goes up...maybe it's worth me taking a moment why that matters.

Rhonda: Yeah, probably explain that.

Peter: So most of these things, as maybe the listeners know when you have hormones floating around the body, whether it'd be testosterone, whether it'd be cortisol, whether it be thyroxine, these things, because they're typically hydrophobic, they can't just travel through the bloodstream freely. They have to be bound and carried just as cholesterol does. And so it's these binding proteins that we often don't think about that play an important role in determining how much active or bioavailable hormone is free.

So in the case of IGF-1 it gets trafficked by this IGF binding protein, and most of these binding proteins actually bear an unbelievable relationship to insulin. So sex hormone-binding globulin goes up when insulin goes down. It's very interesting, there's always this complaint that free testosterone levels will drop, all things equal, in someone who restricts carbohydrates. And I remember through hearing that empirically and not really thinking much about it until I started to, one, observe it and, two, understand why. And it's quite obvious because again, all things equal, when insulin goes down, which is usually what happens when you restrict carbohydrates, sex hormone-binding globulin goes up. That means if you have no change in testosterone level or even estradiol level, free testosterone will go down. Less testosterone is around to be unbound to the sex hormone-binding globulin.

So it's for that reason that I think that insulin and carbohydrate do play an important role in the IGF pathway. And I also think empirically, not that I like to refer to ecology or epidemiology, but when you look at ecology and epidemiology of cancer, to my knowledge the content of highly refined carbohydrate and sugar is more predictive of cancer in a society than the variety in protein content. In other words, there are cultures that have consumed larger and lesser amounts of protein that have been without mass amounts of cancer, but the same cannot be said with large amounts of these things.

Now by these things, I mean sugars and high-glycemic-index carbohydrates. The problem with that is, of course, you can't infer cause from that, but the negative to me is suggestive that at the very least, carbohydrate content matters when it comes to IGF-1 signaling.

Rhonda: Absolutely, and the way I like to think about it actually when you're discussing these two things is IGF-1 is not a cancer initiator, like, it's not going to cause the initial damage that can make a normal cell aberrant, a normal cell that acquires whatever problems it acquired to make it turn into a cell that's not cancer. What IGF-1 is really good at doing is taking that cell that's already acquired the damage.

Peter: It's an amplifier, yeah.

Rhonda: Right. And saying, "Here, keep growing. Like, no, don't die. I know there's signals in your body that are trying to kill you, but don't die." You know, whereas the refined carbohydrates, the way I always think about is that leads to a variety, a plethora of physiological processes in your body, inflammatory processes a lot of different pathways that are causing damage, that are initiating the type of damage. So it's like, well, if you have someone that's eating a terrible diet, they're eating refined carbohydrates, they're they're releasing endotoxin in their gut, they've got this some constant inflammatory process going on, they're releasing hypochlorite damage they were damaging mitochondria, damaging DNA, blah, blah, blah. Well, and then so they've acquired all these damaged cells and then they're eating a bunch of protein and activating the IGF-1 pathway, it's like dynamite. It's like, here's the damage cell and here's the signals to, like, keep living and keep growing. So I kind of...

Peter: Yeah. I mean, so you obviously alluded to this and I think many patients when I talk to them are sort of surprised to learn that every one of us has cancer. I mean, at this moment I have millions of cancer cells in my body, as do you. The good thing is virtually all of the time the problem gets eradicated, right? So either we talk about the apoptotic pathways that you describe, but even when those pathways fail our immune system is remarkable. I did my post-doc in immunotherapy so I spent about two and a half years working with T cells specifically regulatory T cells in looking at this problem, and we just take for granted how good the humoral...the cellular immune system is, rather.

So for those, again, maybe not familiar with the immunology you have your B cell system and your T cell system. These T cells, which are the ones that fight viruses, are unbelievable. When you think about how many antibiotics we have in our arsenal to fight bacterial infections, it's remarkable. Think about how many antiviral drugs we have relative to antibiotics. We have very few and we certainly don't have them for the most common viruses we acquire. And yet, virtually all of us recover in the end unharmed from the typical viral infection we get two to three times a year. That's a testament how amazing our immune system is. And when you unleash it against cancer, it's effective 99.9% of the time. So, yeah, the name of the game is avoid the amplifiers.

Now, the other reason why I think this is an important concept that goes beyond cancer but now gets to the broader aspect of aging is, when you look at the people who live the longest, when you look at these people who live to 100 and beyond, for the most part they die of the exact same diseases as the rest of us schleps. They just get them later. That's really important because I think it offers an insight into longevity that is often overlooked. So if the people who lived to 100, 105 were all dying in car accidents and plane crashes, you might make the argument that there's two classes of citizens, right? There's the people who get chronic disease and then there's people who will never ever, ever get it and eventually they just die of something else. Because remember, the fourth leading cause of death or the fifth leading cause of death starts to become accidental stuff, once you get outside of the chronic stuff, but that's not the case.

The point is we're all, sort of, preprogrammed to go through this process, but if you want to live longer the name of the game is delaying the onset of the big three, the big three being the diseases that will kill 75% of us, so cerebrovascular and cardiovascular, cancer, and neurodegenerative. And so that brings us back to why we've got to have IGF and mTOR in check, because we've got to prevent them from being able to, sort of, amplify that.

Rhonda: Right. And...

Peter: I still haven't answered your question which is, "How do you do this with diet?" But...

Rhonda: Well...

Peter: So I will explain conceptually how you do it. How you do it at the individual level is empirical and I think prescriptive, meaning you have to be able to try something, iterate on it, and make a measurement. But here's the conceptual way to do it. The conceptual way to do it, at least the way I do it, is you consume more or less the least amount of protein you can consume to maintain and grow muscle mass. But you don't need any more than that. So it depends on the individual, it depends on the timing of that protein ingestion, the quality of that protein and the type of metabolic and conditioning stimulus you put into it, but there's an amount. But for most of us I think we're probably over consuming protein relative to that actual need, so we raise protein level until we hit that amount.

Carbohydrate, we do the opposite. Carbohydrate, we are basically lowering it until we reach the highest point...or pardon me, the lowest point that we can tolerate where we can maintain, and again, this is quick and dirty but it's the lowest possible fasting insulin. And in my mind I typically like to see that at below 3 or 4 as IU of insulin. And you want to limit, sort of, post-meal glycemia. And I actually use a standardized test which is an OGTT which has its limits because it's liquid, you're drinking liquid glucose. I like to limit that postprandial hyperinsulinemia to a number and I use a checkpoint of 30 that I want to be able to see within one hour of a 75-gram glucose challenge if you can keep insulin below 30.

So in my mind, because I can't do what's called an AUC, an area under the curve. So the really rigorous way to do this would be I'd put a catheter in your arm and I would sample your blood every 30 or 60 minutes over the course of a day while you ate. And I'd integrate that function and there would be an area under the curve of insulin, and that's actually the number I care about. But since I can't do that outside of a research setting, I rely on these other proxies. So the bottom line is your carbohydrate content is highly variable by the individual, by their insulin sensitivity, by their muscle mass and their capacity to dispose of glucose and a host of other factors. But the bottom line is you don't want to consume any more carbohydrate than you can without blowing through those parameters, and you don't want to consume any more protein than you need to to preserve that. And then basically, fat becomes the fill.

And so the point here is that that becomes a highly different diet for different people. For some people that's 40% carbohydrate and 20% protein, and the remainder of fat. For others that's 20% carbohydrate and 15% protein and the remainder of fat.

Rhonda: So your approach seems to really look at insulin response. It's looking at obviously the IGF-1, mTOR, dietary nutritional factors that are influencing those pathways and then, of course, the rest being fat. For me, I like to think about food as what you're putting in your body not only to activate these pathways or try to keep the pathways from being too active. But also, I like to think about it at the level of the gut because the gut, one, regulates the immune system, big time. I mean that's you've got more immune cells in your gut than you do in any other organ of your body and your gut bacteria, the interaction between your gut bacteria and your gut are also, you know regulating the types of immune cells that you're making, regulatory T cells being put in that.

And also because it's the major source of inflammation, and inflammation,even very recently has been identified to be a driver of the aging process. So eating things that are good for your gut like fiber and avoiding things that are going to cause a lot of gut damage. So I think about those things as well. And then micronutrients which is also a very important. Micronutrients are cofactors for a variety of enzymes and proteins in the body. It makes sure they're functioning proteins that are involved in these processes we're talking about, keeping cancer cells in check. You know, like p53 zinc-dependent proteins, magnesium which is important for repairing damage, things like that. Are those things that you consider at all when you're thinking about the influence of diet on the aging process?

Peter: I don't think about it as much as a lot of people do. And I would hate to use the term I'm a gut skeptic because I think that conjures up a whole bunch of negative images but...so I'm going to be a late adopter on this one, all right? So there are a whole bunch of facts that everybody can rattle off about the gut. A lot of them by the way are kind of BS. So the cells in the gut outnumber the cells in our body 10 to 1, that actually turns out to be false.

Rhonda: So you mean bacterial cells?

Peter: Yeah, sorry, the bacterial cells within our gut. So putting all that stuff aside, there are a whole bunch of really interesting facts. But it reminds me of what a good friend of mine once told me when I was trying to rationalize something I needed to do or thought I needed to do to him. He said, "Why are you doing this?" And I said, "Blah, blah, blah." And he said, "That's a fact, but is it a reason?" And so that's kind of how I feel a little bit about the gut. Like, there's a whole bunch of really interesting stuff but I don't know that it actually matters that much, right?

I'll give you a really idiotic example. The number of ants on this earth outnumber us 10 to 1. I'm making that up. Ergo, we should be doing more to protect the ants by avoiding climate change.

Rhonda: Yeah, but that's irrelevant.

Peter: And I'm saying, "No, that might be true. There might be more ants than us, but we're the species of interest." So that's my first, sort of, kind of, lack of interest. The second is I don't really know what to do with it, right? So I've been through it all, I've gone through all the sequencing, I've done it with patients, and I have found that it's like there's a very crude set of tools that I can use in really obvious cases.

So, all right, a patient that came to me two years ago who had a history of sinusitis, horrible history of sinusitis. So she probably had to do an Augmentin course six times a year because of recurrent sinusitis. She had three surgical procedures, just couldn't get better. So I started working with her. It became pretty clear to me that there was something in her diet that was creating an inflammatory environment that wasn't a structural problem. So we made a lot of dietary changes, things got better, but in parallel to that I sort of suspected that 10 years of 6 cycles of Augmentin probably altered her gut.

And so, yeah, she's an example of someone where I would do a sequence and can be like, "Lo and behold, you're all yeast." Right? Not surprisingly, and disproportionate bacterial overgrowth. Okay, so she's an example of someone in whom the signal was so big that I felt like there was an intervention I could make which was both fixing her diet but also utilizing agents that could alter that. But for the most part, I don't have a clue what to do. And all the people I see who claimed to know what they do, like, they can't convince me that they're knowing what they're doing.

Now, that doesn't mean that you can't...I mean I'm talking outside of a couple of really amazing examples. So we're familiar with how C. diff colitis works and the reversal of C. diff with stool transplants. So those are remarkable examples, but some of the other stuff I'm still not clear of. So I guess what I'm saying is I'm happy to be convinced but I'm not convinced yet that this is a reason and not just a fact.

Rhonda: So I think that focusing on the gut microbiome and the number of bacterial cells that supposedly outnumber our human cells and all that, I don't think that's the important point. You know, so I've become very interested in the gut mostly because of a colleague of mine, Mark Shigenaga, who has been working doing gut research at Children's Hospital in Oakland, and is brilliant. He's been showing me data and I've just been convinced more and more that gut health, making sure that you're keeping the mucin which you're gut goblet cells are producing that disgustingly slimy mucus-like material that's keeping and separating the immune cells in your gut from all the microorganism in your gut. And that's very important because when that starts to break down, the immune cells recognize bacteria and they start [crosstalk]...

Peter: Is there...and I'm not asking this rhetorically, I just don't know. Is there an effective way to diagnose that in patients?

Rhonda: So the problem is that endotoxin released into the blood system would be the way to measure it and to diagnose...

Peter: I see, so you could measure it through the lack of barrier basically.

Rhonda: You can measure the endotoxin levels in someone's blood which is a marker, a proxy, if that helps.

Peter: Yeah, like the throughput, yeah.

Rhonda: But the problem is that there's also a lot of false positives. So that's the only concern until that test, the diagnostic test can be defined...

Peter: Because it seems to be a stool test would be a more effective way to measure that.

Rhonda: Mucin?

Peter: Mucin.

Rhonda: Yeah, there might be. There might be a way to do that, to measure it in a stool. That would be an interesting thing to explore because the...so what I'm getting at here is I'm a scientist, obviously, you're a scientist and like to understand the mechanism and see solid data before you think something is true. And I've become more convinced that the endotoxin released from the gut which is a constant...I mean, really the major source of inflammation in the body is coming from the...

Peter: And to be clear Rhonda, I'm not disputing that. So to be clear, I bought that thesis actually when I was a surgical resident because we would see endotoxemia, right? A surgical procedure gone bad endotoxemia, ICU, death. I know what that looks like in its most extreme state. What I think I'm more of a skeptic of, and again, a skeptic waiting to be convinced, is that I can make that diagnosis in a non-catastrophic case which is basically the chronic case and make an intervention either through some alteration in the microbiome itself or meaning directly or indirectly through diet or other variables. And I think that it would be very interesting, sort of, path to go down but, again, there's so many things I don't know at the moment, I'm just trying to focus on the ones that I do know.

Rhonda: Yeah. There is some interesting work coming out of, like, Justin and Erica Sonnenburg Lab over at Stanford. I recently had a discussion with them on looking at the role of fiber and certain types of fiber in fueling different species of bacteria in the gut and how those are generating short-chain fatty acids and other signaling molecules which are regulating hematopoiesis, they're regulating the number of Tregs that we're making. So it is very interesting that feeding our gut certain types of fiber which are present in vegetables and a variety of fruits even, do have a positive effect on the immune system via the signaling molecules that are being made in the gut.

So that's very interesting, and it is one thing that I consider when I'm thinking about the effects of diet on longevity. You know, I've focused on insulin for a long time. I've been very interested in insulin. When I was doing research at the Salk Institute in La Jolla, before I went to graduate school, I was working on aging and specifically doing different genetic manipulations in C. elegans to look at the effects on aging. So insulin signaling was like obvious. Decrease insulin signaling you're gonna increase this worm's lifespan by, like, up to a 100%, which was, like, very profound.

So I've been very focused on insulin for a long time...reducing the insulin signaling pathway, reducing the insulin response all that. However, I think that as I continue to look in humans we're very complex organisms and there's lots of interactions between the things going on, between different things that are happening in our diet, in our lifestyle that are affecting the way we age. And one of those I do think is gut health. I, sort of, began to become interested in what sort of diet is good for my gut and what is not good for my gut. And I think we were talking a little bit about this before we start filming this, and that is one thing I'm also very interested in these, the effects of fat on the gut. Because fat can be very hard on the gut but I think that also depends on a variety of factors, if you're eating it with protein if you already have an unhealthy gut, if you're not exercising or you are exercising, things like that. Also, genetic factors play a very important role certain polymorphisms in...

Peter: Don't ask me about ApoE.

Rhonda: PPAR gamma?

Peter: Yeah.

Rhonda: Influence saturated fat versus polyunsaturated. Yeah, ApoE. I've actually got one ApoE4 allele, so I'm very interested in ApoE and I'm actually writing a paper on ApoE4 and its role in Alzheimer's right now.

Peter: Well, I'll tell you my take on that, which I'm sure you've seen the literature on it. But I actually think it's the phenotype that matters more than the genotype. So in other words, I think it's the amount of ApoE that's expressed that matters, not the ApoE, not the genotype. In other words, just as we measure ApoB as a surrogate for LDL particle number and VLDL and remnant VLDL particle, we can measure ApoE now. There's no clinically used or CLIA-approved assay for that yet, but there are labs that are doing it for experimental purposes. And there's a paper that I saw maybe six months, nine months ago that actually showed that if you take the ApoE 3/4s and 4/4s...so I'm sure better than I do, a 3/4 genotype just on a hazard ratio is about a 2x increase over the 3/3 in terms of Alzheimer's disease. A 4/4 of course, is anywhere from 10x to 20x depending on the series.

Okay, so if you're out there and you've got an ApoE 3/4, or especially if you've got a 4/4, you're worried, right? And I'm worried for my patients who are 4/4s. I have four patients who are 4/4s. But when I saw this paper what it showed was actually...and just so the listener would know, the majority of people with Alzheimer's are not 3/4 or 4/4, they're still 3/3. The difference is this...because remember, the 3/3 is the majority of the population. I mean the 3/4 is actually pretty big, it's about 20%. But the 3/3 is the largest one, so having a 3/3 doesn't protect you from Alzheimer's and having a 3/4 doesn't guarantee you're going to get it. And, by the way even a 4/4 doesn't guarantee you're going to get it.

So the key is there's something else that's more predictive, and I think it's the phenotype. So when they measured the serum level of ApoE it turned out to be more predictive of Alzheimer's disease than the genotype. So my hope is that we can get a clinically approved assay in a relatively short period of time that will allow us to actually do that, especially for the patients who are 3/4 and 4/4, which says, "Are you able to reduce your risk?"

So let's say I could measure you today and your ApoE level was here. And then we could say, "Well, look, there's some intervention. We believe that reducing or increasing insulin sensitivity of your brain, you know reducing the probability that pyruvate dehydrogenase is going to cause an energy shortage in your neuron is going to improve your odds for delaying or eliminating AD from the list." And then we could measure your ApoE at a point in time and it were lower, that would give me some confidence that we're moving in the right direction because...

Rhonda: Lower? So you're saying that the higher the...

Peter: The higher the expression, the higher the risk. That's what this...

Rhonda: Higher expression in the plasma.

Peter: In the plasma, the higher the risk.

Rhonda: Okay, So a couple of things, one is...

Peter: I'd be happy to show you the paper because that's...

Rhonda: Yeah, that's interesting because from my understanding, you make ApoE in the liver and you make it in the astrocytes. But one of the important things is that it plays an important role in bringing cholesterol...

Peter: Cholesterol. Yep, yep.

Rhonda: ...from the astrocytes to the neurons, but also in repairing damage that's done. So, you need to have neurite outgrowth to repair any sort of damage that's done, damage with normal brain aging or traumatic brain injury, which is like damage in real-time. I was under the impression that there's less...so there's less ApoE expression in ApoE4 and so there ends up being a problem because the LDL receptor is very important for bringing the cholesterol to the neurons, to getting it there and so... But the plasma, I don't know.

Peter: Yeah. And the other thing is I think the...and by the way, I could be wrong. It's been nine months since I read this paper, so I could have it backwards. But I think the more important thing is, I think there's two separate things going on, right? So the ApoE4 gene also plays a role in...because my real interest clinically is, of course, lipidology, that's my clinical obsession. And that's the place where I think we're becoming pretty clear now that the ApoE 4/4 or the 3/4 is not a death sentence in cardiac disease, especially the 4/4. The 4/4 was really viewed as, "Boy, you're guaranteed to have an MI before 60." And I think the evidence today suggests that once you normalize and correct for LDL particle number or ApoB, it stops mattering.

Rhonda: Yeah. Those are definitely probably more important.

Peter: Yeah. And so loosely speaking, this is an oversimplification, if you're a 3/4 or 4/4, in theory you should have a harder time clearing LDL particles from circulation. But I think that that's not entirely the issue that you're alluding to, right? I think there's two issues you're talking about. One is the clearance issue and then one is the cholesterol transport, the central part.

Rhonda: Yes. I mean, and there's also the different issues in the brain versus the liver. So, I mean, we're talking about, like, the astrocytes are almost like little livers in a way but not really. You know, I think looking at the effects on the brain and then looking at the effects on recycling LDL and all the other things going on in the periphery are different. But by the way, I did just want to mention that between 65% and 80% of all cases of Alzheimer's disease at least, you know...

Peter: At least 4?

Rhonda: At least one has a 4. Between 65% and 80% of all the Alzheimer's cases, so...

Peter: So the majority are 3/4s then?

Rhonda: The majority even have at least one allele. Yeah. 3/4s.

Peter: Yeah. But again, that's...

Rhonda: Having just one allele.

Peter: ...based on the hazard ratio, we know that that's just a numbers game because 20% to 25% of the population is 3/4.

Rhonda: Right, exactly. But the point is is that there's something...

Peter: But the 3/3 doesn't protect you from AD.

Rhonda: No, it doesn't.

Peter: So someone walking around with a 3/3 you shouldn't assume that, "Well I'm never going to get AD."

Rhonda: No, it does not protect you, but there is definitely something...

Peter: Does the 2/2 protect you?

Rhonda: The 2 does actually protect. Yes.

Peter: Yeah. I'm sure that some paper has the histogram of 2/2, 2/3...

Rhonda: It's protective. Yeah, it is. And so it's very...

Peter: Because in cardiac disease it does, and in cardiac disease the 2/4 is about the same as the 3/3. The 2 and the 4 cancel.

Rhonda: Wait, say that again? So the 2/4s is...?

Peter: The 2/4 is about the same as the 3/3.

Rhonda: Oh, good.

Peter: And again, just in hazard ratio.

Rhonda: I found that my mom was 2/4 and it was for the cardiac problem that I was kind of worried. Anyways, okay, that's very interesting. So we're totally going off on this ApoE tangent but it's something that...

Peter: No one is even watching at this point, it doesn't matter.

Rhonda: ...I'm very interested in. But there's a huge, huge component for lifestyle in risk for Alzheimer's disease, particularly with having an ApoE4 allele, and that's where I've become obsessed. You know, I've been looking at mechanism but also looking at the epi studies. Looking at epidemiology, you see certain lifestyle factors for example, drinking. If you're drinking in your ApoE4 because you're inducing damage that you can't repair as well, you're going to fare worse. You know, so anything that's going to damage your body worse, anything that's going to create inflammation...refined carbohydrate, eating a bunch of refined carbohydrates, a bunch of sodas with added sugars. Like, all this stuff that's terrible for you, that's not whole food, that's not something that's nutritious, that's going to cause inflammation. Inflammatory molecules get across the blood-brain barrier.

You know, so blah, blah, blah, and all this damage can continue to occur. So obviously, diet, lifestyle play a very important role in your Alzheimer's risk. And I think that understanding the biology of what ApoE4 is doing because now there's research, a lot of it coming out of UCSF Gladstone Institute showing that in addition to a loss of function with the ApoE4 allele, there's also a dominant negative effect. So apparently, the ApoE4, there's this 2-amino-acid substitution and structurally, if you look at the structure of the protein, it starts to get cleaved. And so it itself starts to accumulate these, like, aggregates that then you get more activated microglia and it keeps, like, spiraling out this whole inflammatory process in the brain. So there's also this dominant negative effect that's going on that's interesting. And you want to understand that as well.

But, yes, Alzheimer's disease is one of the neurodegenerative diseases that are up in the top four or five, like you mentioned, cause...

Peter: Well, it's the top. It's the only neurodegenerative disease that's on the top 10 list of death.

Rhonda: Top 10, yeah. So cardiovascular disease...

Peter: So cardiovascular is far and away number one. It's not even...I mean, cancer in an aggregate is number two, but as an oncologist I, sort of, take an issue with that because cancer's a completely heterogeneic form of diseases. So to put this in perspective, right...so breast cancer, who's not afraid of breast cancer if you're a woman? Breast cancer accounts for 3% of deaths in women. I was shocked to learn that, very low. I would have thought much, much higher.

Now, cancer in women, all cancers, 20%, 21%. Cardiac disease, 22% 23%. So if you're woman, if you ask any woman in the street, "Are you more afraid of heart disease or breast cancer?" I think most women would understandably say breast cancer. And yet, it's dwarfed by cardiac disease by a factor of seven and a half to one.

Rhonda: And we definitely know that diet and lifestyle play a major role in your risk for cardiovascular disease.

Peter: Yeah. I mean, I think there's no place where that's more obvious than actually in Alzheimer's disease for other reasons, which is...

Rhonda: Really? Alzheimer's?

Peter: Yeah. I think so.

Rhonda: More than cardiovascular?

Peter: Well, I mean I say that just based on what I called the existence principle, right? So cardiac disease, I mean I think that's entirely true. I think cardiac disease is inevitable. Right? And, while we've had a deterioration in our lifestyle over the past 40 years, a pretty precipitated and accelerated, sort of, move in the wrong direction on that, it's been largely offset by pretty amazing medical advances. So the three things that have, I think, allowed cardiac disease to remain...in fact, it's actually come down. If you look at the death rate from cardiac disease, it's come down. So it's still the number one killer but it's actually on a downward slope, I mean it's sort of plateauing. But when you look at what, sort of, the three biggest drivers are of cardiac disease, the first one is not disputed. It's smoking. So the data are really clear that if you could only make one behavioral change to reduce your risk of heart disease, it's don't smoke.

The next two are actually, because they are so cross-correlated you can't actually distinguish which one is more important, are hypertension and elevated ApoB or LDL particle number. And, again, ApoB is the single best biomarker or LDL-P to distinguish your risk of cardiac disease. It trumps LDL cholesterol, it trumps non-HDL cholesterol, it trumps triglycerides, HDL cholesterol. Those things don't hold a candle to LDL particle number ApoB. Well, think about it. Think about the advances we've made in the last 40 years on all of those, right? So smoking has gone from 45% of the population to 18% of the population. So we reduced smoking.

Rhonda: In the U.S.?

Peter: In the U.S. that's right. Obviously, we haven't done the same in the developing world. Think of the litany of drugs we have for controlling hypertension and think about the litany of drugs we have to bring down ApoB. So despite enormous improvements in the three big picture drivers, it's still the number one killer. So it's got to be lifestyle-driven but we're blunting the effect of that. Whereas in Alzheimer's disease, we don't really have any pharmacotherapy plays. Like, we're still arguing about what the environmental trigger is. Is it all diet-driven, is it sleep-driven, is it stress-driven, what's the combination of factors? Is it is a virus? Is it prions? I mean I've heard every argument under the sun, right?

But here's what we do know. We know that in the last 50 years, the prevalence of Alzheimer's disease has gone up about 2.5%...per year, by the way. I'm sorry. That's per year. Whereas we know that our longevity has increased at about 0.6% per year over that same period of time. Now, over a 50-year period, a 2% spread per year of prevalence. Actually, I think that might be incidence, now when I think about it. I think it's incidence. And longevity suggests that Alzheimer's disease isn't just the natural response of getting old. There's something driving it.

And even if you accept that part of that increase in incidence is a greater appreciation for the diagnosis, it's hard to argue that makes up the full 2% spread. And to me, that's the most convincing case for why there is something in our environment that's triggering Alzheimer's disease and it is not just the natural consequence of aging.

Rhonda: Yeah. So what are your thoughts as to what are triggering Alzheimer's disease in terms of our environment?

Peter: Yeah. I mean, I think it's probably a combination of things. But the most compelling evidence to me and, again, this is probably, because I'm just a simpleton and I like to start with Occam's razor, is it's very hard to dispute the high association between Alzheimer's disease and Type 2 diabetes and hyperinsulinemia. And so I'm in the camp of which some neurobiologists are, but not all. This is still far from being settled. I sort of view Alzheimer's disease as brain diabetes, and I think if the ApoE genotype as basically just a susceptibility.

So I think anybody can get Alzheimer's disease with any genotype if there's enough insulin resistance, if there's basically enough difficulty in getting glucose through pyruvate dehydrogenase and into the Krebs cycle. So I think it's a neuronal energy problem more...and I think all of the other things we see are results of that. But in terms of what the driver is, I think it's a neuronal energy problem. And I think all of the tau plaque, the neuronal, the synapse stuff, I think those are byproducts.

And I think in animal models there's some very convincing data that you can...you know, I mean you've seen the stuff I'm sure more than I have, right? Simultaneous injection of glucose and insulin can transiently overcome deficit, administration of exogenous BHB can overcome the deficit by bypassing and going straight through alpha-hydroxybutyrate into the Krebs cycle. So where you can reverse the signs and symptoms.

Now, I'm not particularly in this space though I find it really interesting. There's a guy by the name of, Richard Isaacson. Do you know Richard? He's a neurologist at Cornell and he has a practice that focuses on early cognitive decline that utilizes very-low-glycemic-index diets coupled with MCT and stuff. So it's basically like inducing ketosis without a full-on ketogenic diet, which obviously for many people is challenging. And he's seen very promising results. I think he's running a couple of clinical trials as well.

And there's a whole sort of...I don't know what the word to describe it is. But there's a whole network of people out there with all of their interesting data that are, because we don't have controls, we just don't know if this is, like, a performance bias we're seeing or if there's a true impact. But anyway that's sort of my hypothesis, which is I don't actually know what's causing Alzheimer's disease, I don't know how to treat it, I don't know if it's treatable once it's in a late enough stage, but I firmly believe that if you can be as insulin-sensitive as possible, for you as an individual you reduce your risk.

Now, that doesn't mean that the risk ever goes to zero for any of us, regardless of ApoE genotype, but I know that if I have to choose between being very-insulin-sensitive and not-so-insulin-sensitive I'm going to be better off in this camp. And I think that's frankly true for every disease state. There are other things. There's subtle things going on, of course. IGF, of course, just to bring it back to where we were. IGF is really interesting because centrally and peripherally you may actually want them to be in opposite directions. You probably know this, but Amgen had a drug that was an IGF-receptor antibody. It went into clinical trials, phase two trials in pancreatic cancer, advanced pancreatic cancer, and it failed.

Now it failed despite reducing IGF levels at the receptor by 50%. You could argue that that failure implies that reducing IGF is irrelevant, reducing IGF is irrelevant once the tumor burden is established, reducing IGF to only 55% is irrelevant. You could argue 100 different things. What's most interesting is that antibody does not cross the blood-brain barrier. And so today, there is ongoing research, it's all in animals at this point in time, that's looking at giving a diet that actually increases IGF but giving it in the presence of this IGF-receptor antibody.

The point being is can we raise IGF levels totally, primarily centrally, and then block the receptor peripherally. So we ward off cancer and diabetes but we ward off dementia. And actually, there's even evidence, though I think this evidence isn't as strong, that elevated levels of central IGF also are protective against diabetes.

Rhonda: Really?

Peter: Yeah. But, again, the problem is these are animal data so you got to, sort of, take everything with, like, a lot of speculation.

Rhonda: Yeah. So to just, kind of, bring it briefly back to the type, when you're talking about diabetes in the brain being Alzheimer's, what's really interesting to me is the fact that neurons are actually mostly using lactate from astrocytes. Astrocytes are glycolytic. The astrocytes are these brain cells in your brain which are using glucose mostly, or using glucose to generate lactate. Lactate then gets shuttled into neurons, and the reason why neurons like that is because it's thermodynamically favorable, much like beta-hydroxybutyrate which you mentioned, BHB, because it can shunt right into the TCA cycle in the mitochondria...

Peter: But wait, how does the brain outcompete the liver for lactate? So, like, if I made you go out there and do a bunch of burpies, right? So the...I'm blanking on the name of the transporter.

Rhonda: MCT.

Peter: MCT1 or MCT2? Which one is the transporter out of the muscle?

Rhonda: I don't know which one.

Peter: Okay, but the majority lactate is going to be generated in the muscle. So then MCT is going to transport that out. And remember, it's going to go through the portal system...it actually it doesn't go to the portal, it passes through the cava, but it's still passing through the liver. How does the brain managed to get any without the liver taking it all into the Cori cycle, which seems to me the preferential place to undergo gluconeogenesis.

Rhonda: Yeah. So what's weird is that...I don't know the answer to your question. I know that many tissues...and this has been shown through the work of George Brooks at UC Berkeley who actually pioneered the lactate shuttle hypothesis and the theory. But it's been shown that it gets taken up by the liver, it gets taken up by the muscle, it gets taken up by the brain. In fact, exercise itself has been shown to preferentially cause the brain to the take up more...

Peter: Can we measure...I don't know if you read this literature but there was a lot of really interesting work back in the '60s done at Harvard with real fasting experiments. I mean 40-day fasts. So you'd have inpatient subjects given nothing but water and minerals for 40 days. And it was done to basically demonstrate what the steady-state fasting levels of glucose, insulin, BHB, and acetoacetate would be. And it's actually quite interesting, right? So you take a normal person. We'd take you and let's say your insulin level is 10, your glucose level is 95, your BHB level is unmeasurable because you're on a normal diet, and your acetoacetate level is unmeasurable, and then we just fast you.

And it turns out that within about seven days, you'll be at a ketone level of 5 to 7 millimolar, glucose will be down to 3 to 4 millimolar, which is, call it 60 to 70 milligrams per deciliter. And you will stay at those levels in...you know, at the end of the 40 days, they're still in those levels.

Rhonda: So they stay the same.

Peter: So glucose remember really goes away. What's changing is the consumption by the neuron which goes from, at the initial state, being about a 100% glucose...of course, I don't think they were measuring lactate then so we don't actually...

Rhonda: Were they looking at neuron or just brain? Was it astrocytes or neuron...

Peter: They were probably just looking at brain. Yeah. But it would fall to maybe 40% or 50%, the rest of it being made up by the combination of the ketones. And it's interesting that they never went to zero, right? So even to your last day of life, if you're being starved to death, you still have glucose in your blood. And so it's kind of interesting that, like...what percentage of overall brain metabolism do you think is driven by lactate? It must be very, very small and reserved for a very, very specific subset of neurons or astrocytes or...

Rhonda: Well, the astrocytes are using the glucose and they're generating lactate. So the lactate doesn't have to get in.

Peter: So we're not even seeing that, so that might be the issue. So that's probably why the liver doesn't matter because it's...

Rhonda: Yeah, during exercise, I mean. But it has been shown that lactate will cross over the blood-brain barrier during exercise as well. But that is why it doesn't have...

Peter: But the dominant source is...

Rhonda: The astrocytes, yeah. The astrocytes are making it in the brain. And what's fascinating is...

Peter: So astrocytes don't have mitochondria?

Rhonda: They do.

Peter: So why do they make all the lactate?

Rhonda: I think they make the lactate because that's how the neurons are getting their energy. I think that's just the way it works out.

Peter: So it's sort of a Warburg effect. The Warburg effect, of course, to me is interesting because I don't buy the argument that the Warburg is due to defective mitochondria.

Rhonda: It's not. Warburg showed that...I mean he...

Peter: No, there are still a lot of people who think that it's that cancer affects of mitochondria, and that's why the Warburg. But I think it's just that the cancer cell's smart enough and it's optimizing for cellular building blocks, and it sounds like the astrocyte is doing the same thing.

Rhonda: Okay. We have to talk about this.

Peter: For different reason, but...

Rhonda: Yeah, it's really interesting. Okay. So we're totally just hopping around all these interesting topics. But, okay, to finish on the lactate thing, fascinating work, traumatic brain injury also brain aging in real-time, people with TBI are much more likely to get Alzheimer's especially if they have ApoE4. You know, up to 10 times, 20 times, depending on how many alleles they have, but...

Peter: I used to do work with some professionals athletes and for guys in the NFL. If I saw that they were ApoE 3/4...and again this is completely bogus but it's the best I think you can do, I would advise somebody who's an ApoE 3/4 entering the NFL that your number of concussions should be fewer than what is recommended.

Rhonda: Yeah. I would actually go as to saying if you're ApoE with 3/4 that head trauma in general is putting you at high risk for...

Peter: No, I completely agree but, of course, when you've got a guy who's about to make $20 million to play football and he's willing to, like, play until he gets six concussions, maybe you make it three.

Rhonda: Yeah. So back to the lactate thing, very interesting. Yeah, so read up on this, you know. George Brooks, a friend of mine, he's working now with some other physicians at UCLA looking at the effects of actually exogenous lactate on helping treat TBI. Because TBI...

Peter: Why not just exogenous BHB?

Rhonda: Or, yeah, or that, exactly.

Peter: I mean have you see what Dom D'Agostino has done?

Rhonda: I think I've read one of his studies on cancer. I think it was cancer.

Peter: Yeah. You should see Dom's work in TBI.

Rhonda: So this...oh, in TBI?

Peter: Yeah. That's how he got started.

Rhonda: That they're the same?

Peter: He's a neurobiologist.

Rhonda: Oh, okay.

Peter: The only reason he's in cancer now is because...he started out working a neurobiology...

Rhonda: Interesting.

Peter: ...and using TBI models.

Rhonda: I didn't know that. Yeah, but it's the same thing, lactate, beta-hydroxybutyrate, it doesn't matter. They're going through the MCT...

Peter: Yeah, they're completely overcoming head trauma.

Rhonda: Yeah, they're both doing similar things. They're both thermodynamically favorable, they allow glucose sparing, they allow glucose to then be used to make glutathione, which is important in the brain when you have damage. But what's interesting is that TBI also disrupts astrocytes' ability to make lactate. And what I'm wondering when you were talking about...

Peter: But those two might just synergize.

Rhonda: They might.

Peter: Because I also think the trauma causes an oxidative stress, so I think what's happening is pyruvate dehydrogenase is getting interrupted and all of a sudden you're having a transient but violent interruption of energy to the brain. And this is obviously of high interest to the military because of blast injuries, and Dom would know this, so it's absolutely worth talking about this with him. I'm sure the DoD is all over this. I hope the DoD is all over this because the interesting question is, do you have to have the BHB or the lactate in your system at the time of injury to prevent it, or can administration be done immediately following the trauma?

Rhonda: Or is there a kinetics? Is there a certain time? I think because of the fact that it allows glucose sparing which if you have a trauma is...and this has been shown on animal models for TBI, but this was done by putting glutathione transcranially which obviously is not going to happen. But anyways, they could prevent, like, over 50% of the damage because they were able to sequester the reactive oxygen species that start to cause all the damage in the inflammatory pathways that start to get out of control.

So I think that if you allow that glucose to be used for the pentose phosphate pathway within a certain time frame...I don't know what that time frame is. It was something within a couple of hours. Then, independent of allowing you neurons to get this easier source of energy...if the neurons are using glucose because they need energy but the glucose can't be used to repair that damage to the pentose phosphate pathway, I think that's one component of it in terms of the temporal effects, like how soon after the damage.

But anyways, your Warburg thing. I have to just quickly tell you, I spent six years doing cancer metabolism at St. Jude Children's Research Hospital. And I wanted nothing more than to believe that mitochondria were dysfunctional and not...

Peter: Defective, yeah.

Rhonda: Yeah, because that would have made my whole thesis, like, so much easier and I wouldn't have taken six years. But I couldn't find that. I couldn't find that the cancer was causing the mitochondria to be so dysfunctional that that's why they were glycolytic.

Peter: Yeah. There's an amazing paper that Matthew Vander Heiden wrote in 2009 in "Science" with Lou Cantley and Craig Thompson. Really, that's when I, sort of, shifted my point of view on that.

Rhonda: Yeah. Well, you mentioned that cancer cells are using it for...I agree with you, with the fact at you know cancer cells, the reason why they're glycolytic I think also is because it's quicker and they don't really give a shit, like...

Peter: Well, they're optimizing for the building blocks to make more cellular machinery. They're basically saying, "I'm willing to do an inefficient process of getting ATP in exchange for something else."

Rhonda: Yes. But here's my other insight onto this, my other, sort of, theory...

Peter: By the way I'm interested in how to exploit that. In other words, you don't have to know why that's happening to figure out how to exploit that. That's what I'm interested in.

Rhonda: Right. Well, here's what I think, another reason why they've figured out not to use their mitochondria. I think the reason they've figured that out, and this is why I also think why things like anything that will activate pyruvate dehydrogenase or anything like beta-hydroxybutyrate, anything that's going to force the mitochondria to work, right? So like whatever it is because the mitochondria are for the most part, not as active in the cancer cell. I think that anything that's going to force them to work...the reason why cancer cells don't want them to work is because cancer cells are primed to die.

So this is the whole basis, most of the basis, behind how chemotherapeutic drugs work. Cancer cells are primed to die in the sense that our body has increased the amount of all these pro-death signals, pro-apoptotic proteins to say, "Die, die, die." Cancer cells have increased all of the anti-apoptotic proteins and signals and say, "No, I'm not going to die yet." So there are, like, balances here. You know, they're primed to die, they're ready to die. All they need is a little push to the pro-death side, right? So if they have a chemo, that's another activating more pro-death, it's enough to push the balance into pro-death, right?

Well, the mitochondria when they're active, when you're highly metabolic using your mitochondria, you're generating reactive oxygen species.

Peter: Reactive oxygen species. Yeah.

Rhonda: Which are a pro-death signal. And I think that is one of the main reasons why giving DCA, activating the pyruvate dehydrogenase complex, can kill cancer cells. I think that's why ketogenic diets, which are basically forcing the cell to use oxidized fats which require a mitochondria, I think that's also why they're very effective at...

Peter: And so that's interesting, so you would think, then, that all things equal, a ketogenic diet would produce favorable cancer outcomes versus exogenous ketones? In other words, you could produce the same hormonal milieu with both, but in one of them you don't have to undergo the machinery.

Rhonda: So, maybe. Maybe. And the reason I say this is...

Peter: And I find that interesting, I don't know the answer.

Rhonda: Yes. The reason I say that is because cancer cells also want lipids. They like to build more cells and you need lipids to build...

Peter: Yeah, so that might offset it.

Rhonda: So I'm worried about that component of it. However, if you think about normal cells aren't primed to die. So anything that's activating your mitochondria in normal cells isn't going to kill them, and I think that's why it's a much better cancer therapeutic strategy than chemo because chemotherapeutic drugs also kill normal cells, proliferating cells. You've got, your hair, your skin, whatever is proliferating fast like a cancer cell. So I actually think that it's possible that whether that's fat oxidation through more of a ketogenic diet, I think it's something that needs to be tested more. Like I said I do have concerns just because you are giving a cancer cell building blocks for more cells, which of course is always a concern.

But I think that anything that is going to force the mitochondria to become active and generate that signaling reactive oxygen species signaling to death to kill it, is good. It's also why taking supplemental dietary antioxidants when you have cancer is very dangerous because you're blunting that whole signaling pathway, right? You're basically blunting all the reactive oxygen species that are usually signaling for your cells that are primed to die, for the cancer cells to die, and you're sequestering it. So it's like and that's been shown. But it's something that's interesting to think about. And I don't know, it's a possibility, it hasn't been proven, but I think that it's certainly an interesting hypothesis that should be looked at. And for all those people out there that are researching cancer and mitochondria, maybe they will.

Peter: We'll be looking at it.

Rhonda: Great. All right, so I think we've talked about a lot of interesting things. And is there anything else you want to discuss or talk about?

Peter: I mean, I think we could talk about ISIS, but I feel like it takes us a little bit off course, so probably not.

Rhonda: Yeah, probably, probably.